Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V1a and V1b receptor subtypes and the renal V2 receptor subtype. The functions of vasopressin include contraction of uterine, bladder and smooth muscle, stimulation of glycogen breakdown in the liver, release of corticotropin from the anterior pituitary, induction of platelet aggregation and central nervous system modulation of behaviors and stress responses. The V1a receptor mediates the contraction of smooth muscle and the hepatic glycogenolytic and central nervous system effects of vasopressin. The V2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase.
Elevated plasma vasopressin levels appear to play a role in the pathogenesis of congestive heart failure (P. A. Van Zwieten, Progr. Pharmacol. Clin. Pharmacol. 1990, 7, 49). As progress toward the treatment of congestive heart failure, nonpeptide vasopressin V2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance in conscious dogs with congestive heart failure (H. Ogawa, J. Med. Chem. 1996, 39, 3547). In certain pathological states, plasma vasopressin levels may be inappropriately elevated for a given osmolality, thereby resulting in renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure), can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Treatment of SIADH-compromised rats with a vasopressin V2 antagonist has corrected their existing hyponatremia (G. Fujisawa, Kidney Int. 1993, 44(1), 19). Due in part to the contractile actions of vasopressin at its V1a receptor in the vasculature, vasopressin V1a antagonists have reduced blood pressure as a potential treatment for hypertension as well. Thus, vasopressin receptor antagonists could be useful as therapeutics in the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
U.S. Pat. No. 3,860,600 relates to heterocyclo[1,4]benzodiazepine derivatives of the formula: wherein R1 is hydrogen or methylenedioxy attached to adjacent carbon atoms or from one to three members of the group consisting of lower-alkyl, lower-alkoxy, fluorine, chlorine, di-lower-alkylamino, N-lower-alkyl-N-lower-alkanoylamino, hydroxy and benzyloxy; R2 is a member of the group consisting of hydrogen, hydroxymethyl or lower-alkanoyloxymethyl; R3 is lower-alkyl, lower-alkanoyl, α-lower-alkanoyloxy-lower-alkanoyl, benzoyl, benzyl or benzoyl or benzyl substituted by methylenedioxy attached to adjacent carbon atoms or from one to three members of the group consisting of lower-alkyl, lower-alkoxy, fluorine, chlorine, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or hydroxy; and Y is one of the groups: —CH2—, —CH(OR4)—, —CH2CH2—, —CH(CH2OR4)CH2—, —S—, —SO—, —SO2—, —CH═CH—, or (i.e., o-phenylene), where R4 is hydrogen or lower-alkanoyl.
European Patent Application EP 0987266 A1 relates to biphenyl derivatives of the formula and pharmaceutically acceptable salts thereof: wherein A represents a single bond, —CH2—, —CO—, —CS— or —SO2—; B represents a single bond or a group —CH2—; R1 represents a hydrogen atom, —OH, —NR11R12 (wherein R11 and R12 each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), —OCOCH3 or a halogen atom; R2 represents a hydrogen atom or R1 and R2 represent ═O, in combination; R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; provided that the absolute configuration at the position a may be either S or R.
Accordingly, it is an object of the present invention to provide bridged bicyclic amino acid-derived [1,4]benzodiazepine compounds that are vasopressin receptor antagonists. It is an object of the invention to provide a method for using a compound of the present invention for treating vasopressin mediated disorders.